Your Brain on Drugs

Your Brain on Drugs

David Pacchioli

December 01, 2004

Does cocaine work differently in a man's brain than it does in a woman's?

That's one possibility raised by the results of some of Melloni Cook's recent experiments. Cook, a Ph.D. student in biobehavioral health at Penn State, works in the lab of associate professor Byron Jones, one of two Penn State investigators in the College of Health and Human Development awarded a program grant by the National Institute on Drug Abuse (NIDA) aimed at understanding the influence of genetics on responses to cocaine. For her part of a preliminary study, Cook administered the drug to two specially-inbred strains of mice, then looked at the chemical changes it caused in their brains.

"These mice are already known to differ in terms of their behavior in response to addictive drugs," she explains. The strain known as DBA (and nicknamed "Death before alcohol" by lab wags) has shown a strong aversion to the drink. Mice of the C strain, by contrast, will choose to imbibe if given the chance, yet DBAs grow more active when given low doses of alcohol. Since the individual mice in each strain are genetically almost identical, different reactions within a strain are held to be environmental.

In her experiments, Cook looked not at behavior but at neurochemistry. She examined four separate brain regions for cocaine-induced changes in the activity of the neurotransmitter dopamine.

Dopamine is a chemical messenger that facilitates communication between brain cells by shooting the gap between them called the synapse. One of many such messengers, dopamine has been closely associated with both motor function and emotional response; its absence or alteration in the brain has been linked to conditions including Parkinson's disease, depression, and schizophrenia.

Ordinarily, after dopamine is released and reaches its site of action, Cook explains, part of it is metabolized, and part is returned to the release site in a kind of recycling mechanism. Brain researchers have shown that cocaine somehow prevents the "re-uptake" of dopamine by the releasing neuron, leaving more dopamine available in the synapse. This increased presence is thought to be related to the drug's pleasurable effect. In addition, cocaine may affect dopamine's actual synthesis, its release, and its utilization.

In the mouse brains she examined, Cook found differences in dopamine response in different brain regions. In some regions, there was hardly any activity. In others, there was dramatic change. "Because of the many hidden neural pathways," she says, "it's hard to say just what is going on.

More striking, however, were differences in dopamine response between male and female mice within the C strain.

"It wasn't just a difference in degree," Cook says. "They actually went in different directions." In males, dopamine utilization levels dropped after cocaine injection. In females, dopamine utilization levels jumped.

"It could have something to do with the estrous cycle," Cook says. "With humans, in many areas of experimental research, investigators have avoided using female subjects to avoid complications related to the menstrual cycle. The same is true in animal research. So gender is a very important variable that has been neglected.

"If it was just the estrus cycle," she continues, "you would expect to see the same changes in both strains — and we didn't." In the DBA mice, in fact, there were no gender-related differences in dopamine response. Cook has submitted a supplementary proposal to NIDA to investigate the gender question at greater depth.

Meanwhile, she'd like to pinpoint the mechanism for the increased dopamine activity she observed. "It's not enough to say there's more of it," she says. "What's causing it? Is more dopamine being released? Or is it that not as much is being metabolized?" Eventually, she says, project investigators — "I don't know if it'll be me" — will try to coordinate these chemical changes with previously observed alterations in behavior.

The ultimate goal, of course, is a better understanding of cocaine's effects on humans, a clue to the genetic (and environmental) reasons why some people are overpowered by the drug while others seem to take it lightly.

"Some day," Cook says, "and I know it's way down the road, we hope to be able to alter the way this drug works in the brain, to make it less pleasurable and less addictive. To offer something useful for the prevention and treatment of its misuse."

Melloni Cook is a Ph.D. student in the biobehavioral health program in the College of Health and Human Development at University Park. Her adviser is Byron C. Jones, Ph.D., associate professor of biobehavioral health, 210 East Henderson Building, University Park, PA 16801. Jones is a co-investigator on "Chromosome Location of Genes Affecting Cocaine Action," a program grant funded by the NAtional Institute on Drug Abuse. The project's principal investigator is Gerald E. McClearn, Ph.D., Evan Pugh professor of Health and Human Development. Also a co-investigator is V. Gene Erwin, Ph.D., co-director of the Alcohol Research Center at the University of Colorado Health Sciences Center School of Pharmacy.

As a result of her graduate work, Melloni Cook was chosen to serve on the planning committee for the 1995 Gordon Conference on catecholamines in Florence, Italy; she is the first graduate student to be so honored.